Shawn, the Drosophila Homolog of SLC25A39/40, Is a Mitochondrial Carrier That Promotes Neuronal Survival.

Mitochondria play an important role in the regulation of neurotransmission, and mitochondrial impairment is a key event in neurodegeneration. Cells rely on mitochondrial carrier proteins of the SLC25 family to shuttle ions, cofactors, and metabolites necessary for enzymatic reactions. Mutations in these carriers often result in rare but severe pathologies in the brain, and some of the genes, including SLC25A39 and SLC25A40, reside in susceptibility loci of severe forms of epilepsy. However, the role of most of these carriers has not been investigated in neurons in vivo. We identified shawn, the Drosophila homolog of SLC25A39 and SLC25A40, in a genetic screen to identify genes involved in neuronal function. Shawn localizes to mitochondria, and missense mutations result in an accumulation of reactive oxygen species, mitochondrial dysfunction, and neurodegeneration. Shawn regulates metal homeostasis, and we found in shawn mutants increased levels of manganese, calcium, and mitochondrial free iron. Mitochondrial mutants often cannot maintain synaptic transmission under demanding conditions, but shawn mutants do, and they also do not display endocytic defects. In contrast, shawn mutants harbor a significant increase in neurotransmitter release. Our work provides the first functional annotation of these essential mitochondrial carriers in the nervous system, and the results suggest that metal imbalances and mitochondrial dysfunction may contribute to defects in synaptic transmission and neuronal survival. SIGNIFICANCE STATEMENT: We describe for the first time the role of the mitochondrial carrier Shawn/SLC25A39/SLC25A40 in the nervous system. In humans, these genes reside in susceptibility loci for epilepsy, and, in flies, we observe neuronal defects related to mitochondrial dysfunction and metal homeostasis defects. Interestingly, shawn mutants also harbor increased neurotransmitter release and neurodegeneration. Our data suggest a connection between maintaining a correct metal balance and mitochondrial function to regulate neuronal survival and neurotransmitter release.

Human intellectual disability genes form conserved functional modules in Drosophila.

Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules.

Cholecystectomy before, simultaneously, or after ERCP in patients with acute cholecystitis: A protocol for systematic review and/or meta analysis.

INTRODUCTION: Cholecystectomy is the intervention of choice for treating acute cholecystitis; when conservative management does not work, it operates on the patient outside the critical condition. It can be performed together with or after endoscopic papillotomy through endoscopic retrograde cholangiopancreatography (ERCP) when it is concurrent with a situation of cholechodocolithiasis or when there is compression and consequent increase in pressure in the bile duct caused by a calculus jammed in the vesicular infundibulum (Mirizzi's syndrome), with or without jaundice, fever, and pain in the right hypochondrium (Charcot's Triad), which can progress to sepsis of biliary origin. This review aims to assess whether the timing of cholecystectomy (before or after ERCP) interferes with the postoperative period and clinical outcome in patients with acute cholecystitis. METHODS AND ANALYSIS: By searching the MEDLINE/PubMed, Embase, Web of Science, ScienceDirect, ClinicalTrials.gov, CINAHAL, Latin American and Caribbean Literature in Health Sciences, Scopus and Cochrane Central databases, Controlled Trials Registry Randomized clinical trials will be searched to analyze whether ERCP performed before or after open or laparoscopic cholecystectomy (LC) in patients with acute cholecystitis is beneficial or not, through the analysis of postoperative complications. No language or publication period restrictions will be imposed. The primary outcome will be postoperative complications (postoperative morbidity and mortality). Four independent reviewers will select the studies and extract data from the original publications, with a fifth reviewer in case of disagreement regarding the inclusion or not of particular research in the present review. The risk of bias will be assessed using The Risk of Bias 2 (RoB 2.0) tool, and the certainty of evidence will be evaluated using the grading of recommendations assessment, development, and evaluation. Data synthesis will be performed using the Review Manager software (RevMan V.5.2.3). To assess heterogeneity, we will calculate the I2 statistics. Additionally, a quantitative synthesis will be performed if the included studies are sufficiently homogeneous. ETHICS AND DISCLOSURE: Since the present study will review secondary data, previously published and scientifically validated, it will not be necessary to obtain ethical approval. The results of this systematic review will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: International Prospective Registry of Systematic Reviews (PROSPERO) CRD42021290726.

COVID-19 pandemic decreased sleep quality of medical students.

Objective: Medical students are especially vulnerable to situations of poor sleep quality due to academic demands. The COVID-19 pandemic brought significant changes and high psychological stress, causing a great impact on this population. Here we aim to analyze the influence of the pandemic on the sleep quality of medical students. Methods: Cross-sectional, observational, and descriptive study with a quantitative approach carried out with students from medical universities in Rio Grande do Norte state (Brazil) through the online application of two questionnaires: Pittsburgh sleep quality index (PSQI-BR) and sociodemographic questionnaire (SQ). Results: A total of 142 medical students participated in this study: 103 women and 39 men. We observed a prevalence of low sleep quality in 78.16% of the sample and that the pandemic significantly affected the sleep quality among medical students (p<0.05). We also found an alteration in the sleep pattern in 83% of the participants, mainly due to anxiety symptoms (38%). Finally, we observed no statistically significant difference in sleep quality or sleep patterns between genders or college period (p>0.05). Discussion: This rate of poor sleep quality is higher than the prevalence of periods before the pandemic (58%). Concerns about COVID-19's negative impact on medical education, delayed training, and impact on the generation of medical jobs can directly aggravate the sleep quality. Conclusion: The COVID-19 pandemic negatively influenced the sleep quality of medical students, increasing the prevalence of poor sleep quality and promoting changes in the sleep pattern.

Parkinsonism secondary to ventriculoperitoneal shunt in a patient with hydrocephalus.

BACKGROUND: Parkinsonism secondary to the treatment of obstructive hydrocephalus due to stenosis of the cerebral aqueduct, with implantation of a ventricular peritoneal (VP) shunt is a rare complication, still poorly described and disseminated in the literature. CASE DESCRIPTION: A 38-year-old male presented a history of moderate-intensity daily headache, which deteriorated 2 months before admission, with no changes in the neurological examination. Magnetic resonance imaging showed hypertensive hydrocephalus associated with cerebral aqueduct stenosis. A VP shunt was performed, an adjustable pressure valve was successfully inserted, and he was discharged asymptomatic. However, months later, he progressed with important symptoms of hypo- and hyper-drainage, which persisted after valve pressure adjustments and even its exchange, culminating into an endoscopic third ventriculostomy (ETV). But soon after, severe Parkinsonian syndrome appeared. Therapy with levodopa and bromocriptine was initiated, revealing a slow response initially but good evolution within 6 months. At present, he presents low-intensity residual tremor, which is well controlled with medications, and has regained independence for daily activities, with minimal motor limitation and no cognitive changes. CONCLUSION: There is still no mechanism that explains the occurrence of Parkinsonian syndrome in these cases. It is suggested that the rostral portion of the midbrain was injured due to abrupt changes in the transtentorial gradient pressure after the ventricular shunt, along with various adjustments in the valve pressure. ETV and early introduction of levodopa therapy in patients who developed postventriculoperitoneal shunt Parkinsonism seems to be the most effective combination, with satisfactory clinical response in the medium/long term.

Knowledge levels among elderly people with Diabetes Mellitus concerning COVID-19: an educational intervention via a teleservice.

AIM: To investigate knowledge levels concerning COVID-19 in elderly patients with T2DM. METHODS: This cross-sectional, quantitative, observational, and descriptive study was undertaken among elderly individuals with T2DM involved in a body balance rehabilitation program that had been suspended due to social isolation. The study participants comprised elderly individuals with T2DM, contactable using fixed or mobile telephones. Data concerning participants' socioeconomic variables and knowledge of COVID-19 were collated, using a Brazil Ministry of Health guidelines checklist. Mann-Whitney and Spearman's correlation tests were used to analyze their responses. RESULTS: Of 30 elderly participants, 76.7% were women and 63.3% were married. The average age was 69.96 ± 4.46 years. The most cited information medium was television (96.6%). Of a possible 24 correct responses on the checklist, the median correct response score was 7.5. No significant relationship was observed between the total checklist score and the variables studied. CONCLUSION: Elderly participants did not have in-depth knowledge concerning COVID-19, which suggests that their knowledge sources may be deficient or that their capacity to retain information was inadequate.

Disposição histórica das internações por Acidente Vascular Cerebral Isquêmico no Nordeste brasileiro entre 1999-2019 / Historical disposition of hospitalizations for Ischemic Stroke in Northeast Brazil between 1999­2019

O objetivo foi analisar a disposição histórica das internações por Acidente Vascular Cerebral Isquêmico (AVCI) e suas características hospitalares dos últimos 20 anos no nordeste brasileiro, hipotetizando o impacto da criação de políticas públicas nacionais. Trata-se de um estudo ecológico retrospectivo de série temporal entre 1999-2019, baseado em dados coletados no Sistema de Informação Hospitalar (SIH) do SUS (DATASUS). Os dados foram estratificados por sexo e faixa etária, e observou-se grande redução do número de internações, valor total (custo) e número de óbitos entre 2001-2002 e entre 2013-2014; os demais anos apresentaram graus proporcionais de constância, sem alterações importantes. As mesmas variáveis aumentaram com a idade, mas mostraram-se equivalentes entre os sexos. Concluiu-se que dados estudados sobre AVCI indicaram declínio acentuado nos anos de 2002 e 2014. Inúmeros fatores podem ter influenciado essa mudança de comportamento, incluindo a implementação de programas como o Hiperdia e Mais Médicos.

The aim of this study was to analyze the historical disposition of hospitalizations for ischemic stroke and their hospital characteristics over the last 20 years in northeastern Brazil, hypothesizing the impact of the creation of national public policies. This is a retrospective ecological study of time series between 1999­2019 based on data collected in the Hospital Information System of the SUS. The data were stratified by sex and age group. There was a significant reduction in the number of hospitalizations, total value (cost), and number of deaths between the years 2001­2002 and 2013­2014; the other years show similar constancy. The same variables increased with age, but were found to be equivalent between genders. The data studied for IS showed a sharp decline between 2002 and 2014. Numerous factors might have influenced this change in behavior, including the implementation of programs such as Hiperdia and Mais Médicos.

Fatores sociodemográficos e clínico-funcionais em idosos com diabetes mellitus tipo 2 pré-frágeis e frágeis relacionados ao baixo nível de atividade física / Sociodemographic and clinical functional factors in pre-frail and frail older adults with type 2 Diabetes Mellitus in relation to low levels of physical activity

OBJETIVO: determinar os fatores sociodemográficos e clínico-funcionais relacionados com o baixo nível de atividade física (BNAF) em idosos com diabetes mellitus tipo 2 (DM2) pré-frágeis e frágeis. MÉTODO: trata-se de estudo observacional, analítico, de caráter transversal. A amostra foi composta por idosos com idade igual ou superior a 60 anos e com diagnóstico clínico de DM2 atendidos no Hospital Universitário Onofre Lopes (HUOL). Foram avaliados dados sociodemográficos e clínico-funcionais com os seguintes instrumentos: Timed Up and Go (TUG), Mini Exame do Estado Mental (MEEM), Geriatric Depression Scale (GDS) de 15 itens, Questionário Internacional de Atividade Física (IPAQ) e fenótipo de fragilidade. Foram utilizados os testes de Qui-quadrado e Mann Whitney para análise dos dados. RESULTADO: a amostra do estudo foi composta por 113 indivíduos classificados como pré-frágeis (52,2%) e frágeis (47,8%). O BNAF foi verificado em 79,6% da amostra. As variáveis que apresentaram diferença estatística significante com o BNAF foram: anos de escolaridade (p=0,02), participação social (p=0,005), insulinoterapia (p=0,02), dor em membros inferiores (p=0,03) e sintomas depressivos (p=0,04). Também, foram encontradas diferenças significantes entre o BNAF e idade (p=0,04) e anos de escolaridade (p=0,05). CONCLUSÃO: O BNAF está associado a alguns fatores sociodemográficos e clínico-funcionais, sendo alguns destes modificáveis e, identificá-los é relevante para elaboração de intervenções em saúde adequadas para prevenção e tratamento tanto do DM2 quanto da Síndrome da Fragilidade (SF).

OBJECTIVE: To determine the sociodemographic and clinical-functional factors related to low levels of physical activity in pre-frail and frail older adults with type 2 diabetes mellitus (DM2). METHOD: an observational, analytical, cross-sectional study was performed. The sample consisted of older adults aged 60 years or over with a clinical diagnosis of DM2 who were treated at the Onofre Lopes University Hospital (or HUOL). Sociodemographic and clinical-functional data were evaluated with the following instruments: the Timed Up and Go (TUG) test, the Mini Mental State Examination (MMSE), the 15-item Geriatric Depression Scale (GDS), the International Physical Activity Questionnaire (IPAQ) and the frailty phenotype. The Chi-square and Mann Whitney tests were used for data analysis. RESULT: the study sample consisted of 113 individuals classified as pre-frail (52.2%) and frail (47.8%). Low levels of physical activity were verified in 79.6% of the sample. The most closely related variables that showed a statistically significant difference with low levels of physical activity were: years of schooling (p=0.02), social participation (p=0.005), insulin therapy (p=0.02), pain in the lower limbs (p=0.03) and depressive symptoms (p=0.04). Also, significant differences were found between low levels of physical activity and age (p=0.04) and years of schooling (p=0.05). CONCLUSION: Low levels of physical activity are associated with certain sociodemographic and clinical-functional factors, some of which are modifiable. Identifying these is important for the development of appropriate health interventions for the prevention and treatment of both DM2 and the Frailty Syndrome (FS)

Reduced synaptic vesicle protein degradation at lysosomes curbs TBC1D24/sky-induced neurodegeneration.

Synaptic demise and accumulation of dysfunctional proteins are thought of as common features in neurodegeneration. However, the mechanisms by which synaptic proteins turn over remain elusive. In this paper, we study Drosophila melanogaster lacking active TBC1D24/Skywalker (Sky), a protein that in humans causes severe neurodegeneration, epilepsy, and DOOR (deafness, onychdystrophy, osteodystrophy, and mental retardation) syndrome, and identify endosome-to-lysosome trafficking as a mechanism for degradation of synaptic vesicle-associated proteins. In fly sky mutants, synaptic vesicles traveled excessively to endosomes. Using chimeric fluorescent timers, we show that synaptic vesicle-associated proteins were younger on average, suggesting that older proteins are more efficiently degraded. Using a genetic screen, we find that reducing endosomal-to-lysosomal trafficking, controlled by the homotypic fusion and vacuole protein sorting (HOPS) complex, rescued the neurotransmission and neurodegeneration defects in sky mutants. Consistently, synaptic vesicle proteins were older in HOPS complex mutants, and these mutants also showed reduced neurotransmission. Our findings define a mechanism in which synaptic transmission is facilitated by efficient protein turnover at lysosomes and identify a potential strategy to suppress defects arising from TBC1D24 mutations in humans.

Diminuição da Velocidade da Marcha em idosos pré-frágeis e frágeis com Diabetes Mellitus tipo 2 e fatores associados / Gait Speed Decrease in pre-frail and frail elderly with Type 2 Diabetes Mellitus and associated factors / Disminución de la Velocidad de Marcha en personas mayores pre-frágiles y frágiles con Diabetes Mellitus tipo 2 y factores asociados

A Diminuição da Velocidade de Marcha (DVM) é um dado importante no desempenho funcional de idosos e é uma condição clínica encontrada na Fragilidade e no Diabetes Mellitus tipo 2 (DM2). Objetiva-se determinar os fatores sociodemográficos e clínico-funcionais relacionados à DVM em idosos diabéticos pré-frágeis e frágeis. Faixa etária, quedas no último ano e risco de quedas são as variáveis que mais se relacionam; ainda, idade, polifarmácia e o risco de quedas obtiveram maior diferença entre os grupos.

Walking Speed Decreasing (WSD) is an important data in the functional performance of the elderly and is a clinical condition found in frailty and type 2 Diabetes Mellitus (DM2). The objective is to determine the sociodemographic and clinical-functional factors related to WSD in pre-frail and frail diabetic elderly. Age group, falls in the last year and risk of falls are the variables that are most closely related. Furthermore, age, polypharmacy and the risk of falls obtained a greater difference between the groups.

La disminución de la Velocidad de la Marcha (MVD) es un dato importante en el rendimiento funcional de los ancianos y es una condición clínica que se encuentra en la fragilidad y la diabetes mellitus tipo 2 (DM2). El objetivo es determinar los factores sociodemográficos y clínico-funcionales relacionados con MVD en ancianos diabéticos pre-frágiles y frágiles. Grupo de edad, caídas en el último año y riesgo de caídas son las variables más relacionadas; aun así, la edad, la polifarmacia y el riesgo de caídas tuvieron una mayor diferencia entre los grupos.

Método Pilates na pressão arterial de idosos: uma revisão narrativa / Pilates Method on arterial pressure of elderly: a narrative review / Método de Pilates en la presión arterial antigua: una revisión narrative

O objetivo do estudo foi buscar na literatura a influência do Método Pilates na pressão arterial de idosos. Trata-se de uma revisão de literatura científica do tipo narrativa. Foram analisados cinco artigos (três ensaios clínicos randomizados, uma revisão sistemática com metanálise e um texto on-line). Observa-se que o Método Pilates é eficaz na manutenção da pressão arterial de idosos como um coadjuvante a alguma terapia associada.

The aimed of the study was to search the literature for the influence of the Pilates Method on the blood pressure of the elderly. It is a review of scientific literature of the type of narrative. Five articles were analysed (three randomized clinical trials, one systematic review with a meta-analysis and one text online). The Pilates Method is effective in maintaining the blood pressure of the elderly as a coadjuvant to some associated therapy.

El objetivo del estudio fue buscar en la literatura la influencia del Método Pilates en la presión arterial de los ancianos. Se trata de una revisión de la literatura científica del tipo narrativa. Se analizaron cinco artículos (tres ensayos clínicos aleatorizados, una revisión sistemática con metanálisis y un texto en línea). Se observa que el Método Pilates es eficaz en el mantenimiento de la presión arterial de los ancianos como un coadyuvante a alguna terapia asociada.